Although the shift in vaccine development from complete pathogens to individual antigens has led to safer vaccines, efficacy has been markedly reduced. Vaccine adjuvants promote strong adaptive responses to soluble recombinant protein antigens. The proinflammatory effects of toll-like receptor (TLR) agonists such as gram-negative LPS and bacterial CpG DNA has led to evaluation of their adjuvant properties and effects on dendritic cells (Jäger et al. (2002) Curr. Opin. Immunol. 14:178-182; Ko et al. (2003) Clin. Cancer res. 9:3222-3234; Medzhitov (2001) Nat. Immunol. 1:135-145). Most TLR agonists function as adjuvants by stimulating the production of cytokines and the maturation of dendritic cells, thereby linking innate and adaptive immunity.
Yersinia pestis, the causative agent of plague, is a gram-negative organism responsible for approximately 200 millions deaths during three major pandemics. In humans, plague has three forms designated by the nature of the infection: bubonic, pneumonic and septicemic. Whereas bubonic plague is spread via bites from infected fleas, the pneumonic form may be transmitted person-to-person. Without medical treatment, pneumonic plague is a rapidly progressing disease with a mortality rate approaching 100% (McSorley et al. (2002) J. Immunol. 169:3914-3919; Means et al. (2003) J. Immunol. 170:5165-5175).
The use of whole-cell vaccines for plague has raised safety concerns. Immunization with the F1 antigen of Y. pestis and an appropriate adjuvant elicits a protective response that correlates with the titer of anti-F1 IgG antibodies (Davila and Celis (2000) J. Immunol. 165:539-547; Brunner et al. (2000) J. Immunol. 165:6278-6286). A synergistic protective effect is obtained when animals are immunized with both F1 and V antigens or a recombinant F1/V fusion protein (Ciacci-Woolwine et al. (1998) Infect. Immun. 66:1127-1134; Moors et al. (2001) Infect. Immun. 69:4424-4429; Gewirtz et al. (2001) J. Clin. Invest. 107:99-109; Steiner et al. (2000) J. Clin. Invest. 105:1769-1777). Although highly variable responses were observed, a phase 1 clinical trial demonstrated that intramuscular immunization with a vaccine containing F1 and V is immunogenic in humans (Eaves-Pyles et al. (2001) J. Immunol. 1666:1248-1260).
It would be desirable to provide improved reagents, pharmaceutical formulations and methods for producing immune responses against pathogens such as Y. pestis. 